Not applicable
Resistance to currently available antibiotics has created a need for new antibiotic agents. Infections, caused by organisms such as Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium and Enterococcus faecalis, have become increasingly resistant to currently approved antibiotics. For example, significant clinical problems include methicillin-resistant strains of S. aureus, which are resistant to all current antibiotics except vancomycin (a drug of last resort because of severe side effects), and a vancomycin-resistant strain of E. faecium enterococci which is now found world-wide. Even community-acquired organisms such as Streptococcus pneumoniae are increasingly resistant to antimicrobial agents, with a significant number of isolates being resistant to penicillin and extended-spectrum cephalosporins.
The emergence and spread of resistant bacterial organisms are primarily caused by acquisition of drug resistance genes, resulting in a broad spectrum of antibiotic resistance (e.g., extended-spectrum cephalosporin-resistant mutant.beta.-lactamases found in several bacterial organisms). Genetic exchange of multiple-resistance genes, by transformation, transduction and conjugation; combined with selective pressures in settings such as hospitals where there is heavy use of antibiotic therapies, enhance the survival and proliferation of antimicrobial agent-resistant bacterial strains occurring by, e.g., spontaneous mutants. Although the extent to which bacteria develop resistance to antimicrobial drugs and the speed with which they do so vary with different types of drugs, resistance has inevitably developed to all antimicrobial agents (see Gold and Moellering, Jr., 1996, New Eng. J. Med., 335(19):1445-1453).
To prevent or delay the buildup of a resistant pathogen population, different chemicals that are effective against a particular disease-causing bacterium must be available. Thus, there is a need to identify compounds which can penetrate and specifically kill the pathogenic bacterial cell, or arrest its growth without also adversely affecting its human, animal, or plant host.
One avenue for accomplishing this task involves the use of compounds targeting RNA polymerase. Accordingly, what is needed in the art are new compounds which are effective inhibitors of bacterial RNA polymerase and which are useful as antibacterial agents. The present invention provides such compounds along with methods for their use.
In one aspect, the present invention provides antibacterial compounds having the formula:
Axe2x80x94Xxe2x80x94Mxe2x80x94Yxe2x80x94B
or a pharmaceutically acceptable salt thereof, wherein the letters A and B each independently represent a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. The letters X and Y each independently represent a group selected from: 
with the proviso that at least one of X or Y is a bond. In the above group of radicals, the subscript m is 0, 1 or 2; the subscript n is 1 or 2; W is selected from O, Nxe2x80x94OR5, Nxe2x80x94NR1R2, Nxe2x80x94NR1C(O)R6 and Nxe2x80x94OC(O)R6; wherein R1, R2, R3, and R5 each independently represent H, (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl or heteroaryl(C1-C6)alkyl; R4 represents H, OH, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)acylamino, or (C1-C8)heteroalkyl; and R6 represents H, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, or (C1-C8)heteroalkyl. Returning to formula I, the letter M is a divalent linking group selected from: 
wherein the letter U represents a group selected from: 
wherein R7 and R8 are independently H, OH, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6)alkylamino or di(C1-C6)alkylamino; R9 is H, (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl or heteroaryl(C1-C6)alkyl; R10 is H, (C1-C6)alkyl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl; and R11 and R12 are independently H, (C1-C6)alkyl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, C(O)R14, C(O)OR14, C(O)xe2x80x94NR14R15, S(O)2R13 or S(O)2NR14R15; wherein R13 is (C1-C6)alkyl, (C1-C6)heteroalkyl, phenyl or substituted phenyl; and R14 and R15 are each independently H, (C1-C6)alkyl or (C1-C6)heteroalkyl.
In another aspect, the present invention provides pharmaceutical compositions comprising one or more of the above compounds in admixture with a pharmaceutically acceptable excipient.
In yet another aspect, the present invention provides methods for controlling bacterial growth on a surface comprising contacting the surface with a compound having the formula above.
In still another aspect, the present invention provides methods for treating or preventing bacterial growth in a subject by administering to the subject an effective amount of a compound having the formula above.